FDA Issues Guidance on Drug Manufacturing Inspections, Announces Workshops

Date: Nov 02, 2001

On March 29, 2002, FDA announced a series of workshops to discuss the application of its new guidance document entitled:  “Compliance Program Guidance Manual for FDA Staff:  Drug Manufacturing Inspections, ” which was made available on January 14, 2002.  This document, issued by FDA's Center for Drug Evaluation and Research (CDER), announces the long expected “systems” approach to drug manufacturing inspections.  The workshops will be held in collaboration with the Consumer Healthcare Products Association (CHPA), and are intended to provide a regulatory perspective on the systems-based approach described below.  The Workshops will be held in East Rutherford, New Jersey, on June 17, 2002, in San Juan, Puerto Rico, on July 15, 2002, and in Manhattan Beach, California, on August 5, 2002.  For details on the workshops and registration information, see the announcement in the Federal register of March 29, 2002 (67 Fed.Reg. 15210).

Scope of the Guidance

This new guidance is designed to assist FDA inspectors in evaluating compliance of drug manufacturing plants with current Good Manufacturing Practice (cGMP) requirements under Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), thus minimizing consumers' exposure to adulterated drug products (a drug product being automatically deemed adulterated under § 501(a)(2)(B) if not used, manufactured, processed, packed or held in accordance with cGMP).  This guidance is relevant to any company involved in the manufacture of drugs, including manufacturers of bulk active pharmaceutical ingredients, intermediates and excipients.  This is the first half of a broader coverage by FDA of all aspects of production and distribution of drugs and drug products.  The Drug Manufacturing Inspections program addresses drug production, while the Drug Product Surveillance Program monitors the quality of drugs in distribution through surveillance activities such as sampling and analysis.

A 'Systems' Approach

This revised program stems from FDA's acknowledgement that it is not feasible for its inspectors to conduct in-depth inspections of all systems and processes in all drug manufacturing plants on a biennial basis.  The program is part of FDA's reprioritizing of resources.  Although the general policy of biennial inspections is maintained under the program, it is the method by which those inspections are conducted that is modified by the guidance document.  “Inspection” is defined under the guideline as “audit coverage of 2 or more systems, with mandatory coverage of the Quality System.”  The compliance status of a facility will now be determined by sampling the compliance status of a variable number of systems (always including the Quality System) depending on the type of inspection being conducted.  The overall cGMP evaluation of the inspected facility will be based on the sole evaluation of those systems that are actually inspected, as it will be assumed that system deficiencies apply across the board to all product lines manufactured at the site. 

Which Inspections for Which Systems

  1. Inspections
  2. There are two types of inspections conducted by FDA under the revised program:

    Surveillance inspections, i.e., routine inspections conducted periodically; and Compliance inspections, i.e., inspections conducted to verify the adequacy of corrective actions implemented in response to a regulatory action.  Both types can be conducted either as full or abbreviated inspections depending on the circumstances.  Characteristics of full and abbreviated inspections are as follows.

    FullInspection:  This inspection is conducted when little or no information is known about a firm's cGMP compliance, or where there is doubt as to cGMP compliance (arising from a history of violations/deficiencies).  This type of inspection is not routine, and thus is expected to be conducted only every third or fourth inspection cycle (i.e., every 6 to 8 years).  The full inspection normally includes coverage of at least four systems, including the Quality System. 

    Abbreviated Inspection:  This inspection provides an update on previous evaluations of a facility's cGMP compliance, when it has a satisfactory compliance history, no significant problems, and no shift in its manufacturing process within the past two years.  Such inspections can cover as little as two systems, the Quality System and one other.

    Additionally, Compliance inspections can take the form of a For Cause inspection.     This type of inspection is used to investigate a specific problem that has come to the attention of the agency.  This type of evaluation focuses on whatever system is related to the problems that give rise to the “cause.”

  3. Systems
  4. For the purpose of auditing the manufacture of drugs and drug products, the manufacturing process is categorized into six systems:

    1. Quality System

    2. Facilities and Equipment System

    3. Materials System

    4. Production System

    5. Packaging and Labeling System

    6. Laboratory Control System

    The document organizes each cGMP obligation into one of these six systems.  All areas of an audited system are to be covered during the inspection of said system.

    The Systems Inspection

    It is FDA's intent that a proper inspection of a system will result in a report that should be sufficiently detailed, with specific examples, so that the outcome of the inspection reflects the state of quality, identity, strength and purity of the products resulting from that system.  The new approach applies to distributed prescription drug products, OTC drug products, approved products and products not requiring approval, as well as drug products used in clinical trials.  Although the cGMP regulations are not directly applicable to active pharmaceutical ingredients (APIs), they are to be used as guidance for cGMP in API manufacture.  Documented cGMP deficiencies provide the evidence for concluding that a system is not operating in a state of control.  A firm is deemed out of control if any one of its systems is out of control.  Findings that demonstrate that a firm is not operating in a state of control may then be used as evidence for taking appropriate advisory, administrative and/or judicial actions.

    If the inspection plan outlined in the guidance document works as expected, FDA will spend less time determining that a site is in or out of compliance and, hence, will be able to conduct more inspections.  The guidance document can be found at:http://www.fda.gov/cder/dmpq/compliance_guide.htm

    while a copy of the March 29, 2002 Federal Register Notice, containing additional information on the workshops, can be found at:http://www.fda.gov/OHRMS/DOCKETS/98fr/032902e.html

    In addition, the draft guidance and other useful documents and resources to consider in developing a CGMP compliance program, can be found on this website, at:"CGMP Compliance: Making it Happen in a Chemical Facility A CGMP Bibliography"